The reticuloendothelial system (RES) is a network of phagocytic cells called macrophages which are derived from circulating leukocytes called monocytes. These circulating monocytes differentiate into tissue macrophages which become localized to organs including the spleen, liver and lungs. Tissue macrophages engulf foreign bodies and promote their clearance by other components of the humoral immune system. Alveolar macrophages provide a first line of cellular defense against invasion of the lung by inhaled foreign material and pathogens. After tissue injury, compounds are released that promote migration of neutrophils and macrophages to the wound site. These cells then release inflammatory mediators and cytokines including interleukins, complement components, prostaglandins, interferons, peroxides and free radicals which begin an inflammatory cascade. Although this cascade is mostly beneficial as in destroying bacterial pathogens, in some cases it is inappropriately excessive and leads to severe disorders.
Adult respiratory distress syndrome (ARDS) is a serious condition most often affecting the lungs of individuals who have undergone major surgery, trauma or infection. ARDS occurs in approximately 150,000 persons annually with a mortality rate approaching 50%. Lung injury results in leukocyte influx. These leukocytes then release inflammatory cytokines resulting in accumulation of fluid and cellular debris in the pulmonary passages, thus impairing oxygen exchange. There is currently no completely effective treatment for this disorder. Infant Respiratory Distress Syndrome (IRDS) presents similar treatment difficulties. Symptomatic treatment through liquid breathing of fluorocarbons has been proposed as a means to facilitate oxygen delivery and remove accumulations in the lung in ARDS and IRDS. See, e.g., PCT application PCT/US92/03660.
Fluorocarbon (FC) liquids are generally analogous to common organic compounds; however, most or all of the carbon-bound hydrogen atoms have been replaced with fluorine atoms. These compounds are typically clear, colorless, odorless, nonflammable and essentially insoluble in water. When all carbon-bound hydrogens have been replaced with fluorine, the compounds are referred to as perfluorocarbons (PFCs). PFC liquids are denser than water and soft tissue, have low surface tension and low viscosity. PFC liquids and other highly fluorinated liquids are unique in their high affinity for gases, dissolving more than 20 times as much oxygen and over three times as much carbon dioxide as water. PFC liquids are also substantially nontoxic and inert (Riess, (1984) Artificial Organs, 8: 34-56). One example of a widely-used perfluorocarbon is perfluorooctyl bromide (PFOB), also called perflubron. These liquids are commonly used as either neat solutions or emulsions.
Mammals can breathe oxygenated FCs and return to air breathing without long-term effects (Modell et al., (1970) Federation Proc., 29: 1731-1739; Modell et al., (1976) Chest, 69: 79-81). No significant adverse morphological, biochemical or histological effects are observed after FC ventilation (Calderwood et al., (1975) J. Applied. Physiol., 39: 603-607; Forman et al., (1984) Federation Proc., 43: 647). Published PCT application PCT/US91/07142 to Fuhrman describes a perfluorocarbon associated gas exchange (PAGE) method which maintains respiratory gas exchange in the PFC-laden pulmonary air passages by continuous positive pressure breathing using a conventional gas ventilator. This procedure allows more rapid ventilation and is far less cumbersome than liquid breathing. PFCs are effective in rinsing out cellular debris associated with ARDS (Puchetti et al., (1984) Fourth World Congress for Bronchology, abstract, 115) and in treating respiratory distress syndromes involving surfactant deficiency or dysfunction. A number of other biomedical applications for liquid PFCs and PFC emulsions have also been described, including their use as imaging agents and blood substitutes (Riess, (1984) Artificial Organs, 8: 34-56). Liquid PFCs are removed from the circulation by macrophages of the RES.